Background: Axonal misdirection remains a major limitation in peripheral nerve repair. While nerve guidance conduits (NGCs) and nerve scaffolds (NSCs) have advanced structurally, it is unclear whether these designs effectively reduce misdirection compared to autografts (ANGs). This systematic review evaluates the impact of NGC and NSC structural features on axonal dispersion and reinnervation accuracy using retrograde tracing animal models. Methods: A systematic search was performed through Medline (PubMed), Scopus (EBSCOhost), and the Cochrane Library from inception to December 2024. Eligible studies included mammalian in vivo models of peripheral nerve transection repaired by direct coaptation, autografts, or artificial conduits and assessed with retrograde axonal tracing. Data on neurons labeling, innervation accuracy, and histomorphometric parameters were extracted, and misdirection rates were calculated. Risk of bias was assessed using the SYRCLE tool. Due to heterogeneity, data were synthesized narratively following the SWiM framework. Results: Out of 4043 records identified through database searching and 37 through citation searching, 19 studies (49 experimental groups) met the inclusion criteria. Motoneuron counts were consistently reported across all arms, but no outcome assessing axonal misdirection was reported in more than half. Structured designs resulted in outcomes more closely aligned with ANG repair, while unstructured generally underperformed, and certainty of evidence was very low. Discussion: The evidence in this study was limited by high risk of bias, substantial inconsistency across heterogeneous study designs and outcomes, and imprecision from small animal models with sparse outcome measures. Despite the trend for structured designs to improve over basic hollow designs, current evidence does not support any structure as superior. Future research should be more standardized to provide reliable knowledge translational into clinical practice.

Most studies on nerve guidance conduits (NGCs) focuses on advancing biomaterials and enhancing their functionality to outperform autologous nerve grafts (ANGs). However, even when these strategies exceed the ANG effects, they may not guarantee satisfactory recovery in every case, considering their inability to impact the direction of axonal growth. Axonal misdirection occurs due to dispersive nature of axonal growth and variable intraneural branching topography, presenting one of the main obstacles in achieving consistent success in peripheral nerve repair. On the other side, implementation of various NGC structural features may offer a potential solution. This paper reviews the NGC structural designing strategies, and assesses their potential to influence axonal direction, exploring the key challenges and future perspectives. The literature was reviewed using PubMed, ScienceDirect, OpenMD, Cochrane Library, and Google Scholar databases. The simplest single-hollow NGC design may prevent axonal dispersion, however only in small nerve gaps. The multichannel and nanofiber-filled NGC designs provide a neural-like microenvironment and straightforward axonal guidance, supporting successful regeneration in larger nerve gaps. Even though these structural strategies may also surpass the efficacy of ANGs, such straightforward guidance does not exclude the axonal misdirection, due to variable distribution of fascicular trajectories. In the future, this issue could be addressed by intraoperative 3D scanning of the stumps, using the machine learning algorithms to predict the fascicular distribution, and on-site 3D printing of personalized NGCs.